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Dissociation of Antimicrobial and Hemolytic Activities of Gramicidin S through N ‐ Methylation Modification
Author(s) -
Li Yangmei,
Bionda Nina,
Yongye Austin,
Geer Phaedra,
Stawikowski Maciej,
Cudic Predrag,
Martinez Karina,
Houghten Richard A.
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300232
Subject(s) - gramicidin s , chemistry , antimicrobial , hydrogen bond , stereochemistry , circular dichroism , peptide , methylation , antimicrobial peptides , intramolecular force , amide , protein secondary structure , residue (chemistry) , monomer , gramicidin , biochemistry , organic chemistry , molecule , membrane , dna , polymer
β‐Sheet antimicrobial peptides (AMPs) are well recognized as promising candidates for the treatment of multidrug‐resistant bacterial infections. To dissociate antimicrobial activity and hemolytic effect of β‐sheet AMPs, we hypothesize that N‐methylation of the intramolecular hydrogen bond(s)‐forming amides could improve their specificities for microbial cells over human erythrocytes. We utilized a model β‐sheet antimicrobial peptide, gramicidin S (GS), to study the N‐methylation effects on the antimicrobial and hemolytic activities. We synthesized twelve N‐methylated GS analogues by replacement of residues at the β‐strand and β‐turn regions with N‐methyl amino acids, and tested their antimicrobial and hemolytic activities. Our experiments showed that the HC 50 values increased fivefold compared with that of GS, when the internal hydrogen‐bonded leucine residue was methylated. Neither hemolytic effect nor antimicrobial activity changed when proline alone was replaced with N ‐methylalanine in the β‐turn region. However, analogues containing N ‐methylleucine at β‐strand and N ‐methylalanine at β‐turn regions exhibited a fourfold increase in selectivity index compared to GS. We also examined the conformation of these N‐methylated GS analogues using 1 H NMR and circular dichroism (CD) spectroscopy in aqueous solution, and visualized the backbone structures and residue orientations using molecular dynamics simulations. The results show that N‐methylation of the internal hydrogen bond‐forming amide affected the conformation, backbone shape, and side chain orientation of GS.